Benzenesulfonyl-ureas and process for their manufacture

ABSTRACT

Benzenesulfonyl-ureas of the formula   IN WHICH R1 is alkyl or alkenyl of two to eight carbon atoms, cycloalkyl of five to eight carbon atoms, cyclohexyl-lower alkyl, lower alkyl-cyclohexyl, lower alkoxy-cyclohexyl, phenyl-lower alkyl, endoalkylene-cyclohexyl, endoalkylene-cyclohexenyl, endoalkylene-cyclohexylmethyl or endoalkylene-cyclohexenylmethyl having one to two carbon atoms in the endoalkylene moiety, cyclohexenyl or cyclohexenylmethyl; Y is an alkylene of one to four carbon atoms; Z is phenyl or p-tolyl; and X is hydrogen, methyl, chloro or nitro substituted in the four- or fiveposition; and physiologically tolerable salts thereof are disclosed as having utility as orally administrable hypoglycemic agents in the treatment of diabetes mellitus.

United States Patent Helmut Weber Frankfurt am Main;

Walter Aumuller, Kelkheim, Taunus; Rudi Weyer, Frankfurt am Main, Karl Muth, Kelkheim, Taunus; Felix Helmut Schmidt, Mm Neuosthelm,allo1Germany [72] Inventors [54] BENZENESULFONYL-UREAS AND PROCESS FOR THEIR MANUFACTURE 12 Claims, No Drawings [52] US. Cl ..260/553DA, 260/327 TH, 260/347.3, 260/999, 260/345. 7 51 lm. c|.... ..c07 127/00 [50] Field ofSearch 260/553 D, 553 DA [56] References Cited UNITED STATESPATENTS 3,384,757 5/1968 Ruschig et a1. 260/553 FOREIGN PATENTS 654,561 4/1965 Belgium 260/553 815,885 7/1959 Great Britain 260/553 OTHER REFERENCES German Auslegeschrifi No. 1 185 180, l/14/65, Farbwerke Hoechst Aktiengesellschaft.

Primary Examiner-Hemard l-lelfin Assistant Examiner-Gerald A. Schwartz Attorney-Curtis, Morris & Safford ABSTRACT: Benzenesulfonyl-ureas of the formula in which R is alkyl or alkenyl of 2 to 8 carbon atoms cycloalkyl of 5 to 8 carbon atoms, cyclohexyl-lower alkyl. lower alkyl-cyclohexyl, lower alkoxy-cyclohexyl, phenyl-lower alkyl, endoalkylene-cyclohexyl, endoalkylene-cyclohexenyl, endoa1kylene-cyclohexylmethyl or endoalkylene-cyclohexenylmethyl having 1 to 2 carbon atoms in the endoalkylene moiety, cyclohexenyl 0r cyclohexenylmethyl;Y is an alkylene of 1 to 4 carbon atoms; Z is phenyl or p-toly'l; and X is hydrogen, methyl, chloro or nitro substituted in the 4- or 5-position; and physiologically tolerable salts thereof are disclosed as having utility as orally administrable hypoglycemic agents in the treatment of diabetes mellitus.

BENZENESULFONYL-UREAS AND PROCESS FOR THEIR MANUFACTURE The present invention provides benzenesulfonyl-ureas of the formula which in free form or in the form of their salts have blood sugar lowering properties and which are distinguished by a strong and long-lasting hypoglycemic action.

In the above formula R represents hydrogen, low molecular weight alkyl or low molecular weight phenyl-alkyl,

R represents a. alkyl, alkenyl or mercapto-alkyl containing two to eight carbon atoms,

b. alkoxy-alkyl, alkyl-mercaptoalkyl or alkyl-sulfinylalkyl containing four to eight carbon atoms of which at least two belong to the alkylene part of the alkoxy-alkyl, alkyl-mercaptoalkyl or alkyl-sulfinylalkyl group,

c. low molecular weight phenyl-alkyl, phenylcyclopropyl,

d. low molecular weight cyclohexyl-alkyl, cycloheptylmethyl, cycloheptyl-ethyl or cyclooctyl-methyl,

e. endoalkylene-cyclohexyl, endoalkylene-cyclohexenyl,

endoalkylene-cyclohexylmethyl or endoalkylenecyclohexenylmethyl containing one to two carbon atoms in the endoalkylene part,

f. low molecular weight alkyl-cyclohexyl, low molecular weight alkoxy-cyclohexyl,

g. cycloalkyl containing five to eight carbon atoms,

h. cyclohexenyl, cyclohexenylmethyl,

i. a heterocyclic ring containing four to five carbon atoms and one oxygen or one sulfur atom and up to two ethylenic double bonds, or

k. a heterocyclic ring containing four to five carbon atoms and one oxygen or two sulfur atom and up to two ethylenic double double said heterocyclic ring being linked to the nitrogen atom by means of a methylene group,

Y represents a hydrocarbon chain containing one to four carbon atoms,

2 represents a phenyl group which may carry a low molecular weight alkyl group, a low molecular weight alkoxy group or a CF, group or 1 chlorine, bromine, or fluorine atom,

X represents halogen, low molecular weight alkyl, low molecular weight alkoxy, -CF, or -NO, or also hydrogen, the group X preferably standing in the 4- or in the 5-position.

The termlow molecular weight alkyl is used throughout the specification to mean an alkyl radical containing one to four carbon atoms in a straight or branched chain.

In correspondence with the definitions given above, R may represent, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert. butyl, benzyl, aor fl-phenyl-ethyl, a-, )3- or 7- phenyl-propyl. Compounds in which R represents methyl or benzyl and especially those in which R represents hydrogen are preferred.

R may represent, for example, ethyl, propyl, isopropyl, butyl, isobutyl, sec. butyl, straight chain or branched amyl (pentyl), hexyl, heptyl or octyl, furthermore, it may represent radicals which correspond to the aforementioned hydrocarbon radicals and which contain an ethylenic double bond, for example, allyl or crotyl; furthermore alkyls containing two to eight carbon atoms and one mercapto group, for example )3- mercapto-ethyl, or higher mercapto-alkyls. Furthermore, R may represent 7-methoxypropyl, fi-methoxy-n-butyl, B-ethoxyethyl, rethoxy-propyl, S-ethoxybutyl or higher alkyloxyethyls, -propyls or -butyls, and the corresponding groups carrying a sulfur atom or the member -SO- instead of the oxygen atom. Furthermore, R may represent: benzyl, a-phenyl-ethyl, B-phenyl-ethyl, 01-, B- or 'y-phenyl-propyl or phenyl-butyls.

Within the scope of the present invention, there are particularly preferred compounds containing as R a cycloaliphatic hydrocarbon group which may be substituted by alkyl or alkoxy or which may be linked to the nitrogen atom by means of an alkylene group. As examples of such groups, there may be mentioned cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, methyl-cyclohexyl, ethyl-cyclohexyl, propyl-cyclohexyl and isopropyl-cyclohexyl, methoxy-cyclohexyl, ethoxy-cyclohexyl, propoxy-cyclohexyl and isopropoxy-cyclohexyl; the alkyl or alkoxy groups may be present in the 2-, 3- or, preferably in the 4-position, and in the cis as well as in the trans position. Furthermore, there may be mentioned cyclohexylmethyl, aor-B-cyclohexyl-ethyl, cyclohexylpropyls, endomethylenecyclohexyl (2,2,l-bicycloheptyl), endoethylene-cyclohexyl (2,2,2-bicyclo-octyl), endomethylene-cyclohexenyl, endoethylene-cyclohexenyl, endomethylene-cyclohexylmethyl, endoethylene-cyclohexylmethyl, endomethylene-cyclohexenylmethyl or endoethylene-cyclohexenylmethyl, aor B- phenyl-cyclopropyl, in the cis or in the trans form. Finally, R may represent heterocyclic rings which contain, in addition to four to five carbon atoms, one oxygen or one sulfur atom and up to two double bonds and which may be bound to the adjacent nitrogen atom by a methylene group.

Examples of such heterocyclic rings are:

Examples of the bridge member Y are:

The phe nylene radical indicated in the formula by -phen-' yleneis preferably unsubstituted, but may also be substituted by one or more substituents selected from halogen atoms, low molecular weight alkyl groups or low molecular weight alkoxy groups. It may contain the remaining parts of the molecule in o-, mor para-position to one another, the para-position being preferred.

The present invention furthen'nore provides a process for the manufacture of the above-identified benzenesulfonylureas. Thus, the benzenesulfonyl-ureas of the present invention can be prepared by a. reacting benzenesulfonyl-isocyanates, benzenesulfonylcarbarnic acid esters, benzenesulfonyl-thiolcarbamic acid esters, benzenesulfonyl-ureas, benzenesulfonyl-semicarbazides or benzenesulfonyl-semicarbazones carrying the substituerlt with R-substituted amines or their salts;

b. reacting benzene-sulfonamides of the formula I R 0 Z or'their salts with lR -substituted isocyanates, carbamic acid esters, thiolcarbamic acid esters, carbamic acid halides or ureas,

c. hydrolizing correspondingly substituted benzenesulfonylisourea ethers, benzensulfonyl-isothiourea esters, benzenesulfonyl-isothiol-urea ethers, benzenesulfonylparabanic acids or benzenesulfonyl-haloformic acid amidines,

d. fixing water to correspondingly substituted carbodiimides,

e. in correspondingly substituted benzenesulfonyl-thioureas, replacing the sulfur atom by an oxygen atom,

f. introducing by acylation the radical in one or several steps into benzenesulfonyl-ureas of the formula and, if desired, converting the reaction products into salts by treatment with alkaline agents.

Depending on the nature of the group one or more of the aforesaid processes may in certain cases be unsuitable for the preparation of some individual compounds covered by the general formula. These particular cases which are relatively unusual and are easily recognized by the expert, so that it is not difl'icult to select another successful method of synthesis from those described above.

Instead of the benzenesulfonyl-isocyanates, there may also be used reaction products of benzenesulfonyl-isocyanates with acid amides such as caprolactam or butyrolactam, furthermore with weakly basic amines such as carbazols.

The above-mentioned benzenesulfonyl-carbamic acid esters or benzenesulfonyl-thiolcarbamic acid esters may contain in the alcohol component an alkyl group or an aryl group or even a heterocyclic group. Since this group is separated during the reaction, its chemical constitution has no influence on the character of the final products and may, therefore, be varied within wide limits. The same applies to the R-substituted carbamic acid esters or to the corresponding thiolcarbamic acid esters.

As carbamic acid halides, the chlorides are used.

The benzenesulfonyl-ureas used as starting substances in the process of the present invention may be unsubstituted at the side of the urea molecule opposite to the sulfonyl group or may be monosubstituted or, particularly, disubstituted. Since these substituents are separated during the reaction with amines, their character may be varied within wide limits. in addition to benzenesulfonyl-ureas which are substituted by alkyl, aryl, acyl or heterocyclic groups, there may also be used bis-(benzenesulfonyl)-ureas or bis-(benzenesulfonyD-ureas which carry a further substituent, for example, a methyl group, at one of the nitrogen atoms. For example,

advantageously .bis(benzene-sulfonyl)-ureas or also N-benzenesulfonyl-N'- acyl ureas may be treated with cyclohexylamine or with pmethyl-cyclohexylamine and the salts obtained may be heated to elevated temperatures, in particular to temperatures above l C.

C 0 NH-Y- substituted benzenesultonarnides.

As such starting substances, there may be used, for example, N-cyclo-hexyl-urea or N-( 4methyl-cyclohexyl)-urea, the corresponding N'-acetyl-, N'-nitro-, N'-cyclohexyl-, N'-(4- methyl-cyclohexyl)-, N',N"diphenyl- (wherein both phenyl radicals may also be substituted or linked with one another either directly or over a bridge member such as -Cl-l -NlH-, -0- or -S), N'-methyl-N'-phenyl-, N',N'-dicyclohexyl-ureas and Y-substituted cyclo-hexyl-carbamoyl-imidazoles or triazoles.

The hydrolysis of the benzenesulfonyl-parabanic acids, benzenesulfonyl-isourea ethers, benzenesulfonyl-isothiourea ethers, benmenesulfonyl-isourea esters or benzenesulfonylhaloformic acid amidines mentioned as starting substances is suitably carried out in an alkaline medium. lsourea ethers and isourea esters may also be hydrolized successfully in an acid medium.

In the correspondingly substituted benzenesulfonyl-thioureas the sulfur atom can be replaced by an oxygen atom, for example, with the aid of oxides or salts of heavy metals or also by the use of oxidizing agents such, for example, as hydrogen peroxide, sodium peroxide or nitrous acid.

The thioureas can also be desulfurized by treatment with phosgene or phosphorus pentachloride. Chloroforrnic acid amidines or chloroformic acid carbodiimides obtained as intermediate products can be converted into benzensulfonylureas by an appropriate treatment, for example, by hydrolysis or the addition of water.

in analogous manner as the thioureas behave the isothiolurea ethers which, in the sense of the invention, are equivalent as starting substances for the desulfurizing reactions.

The acylation of aminoethyLbenZenesuIt'onyI-ureas may be carried out either in one step, for example, by reaction of correspondingly substituted benzoic acid halides, or it may be carried out in several steps. One example of the numerous possibilities of stepwise acylation is the reaction of corresponding aminoethyLbenzenesulfonyl-ureas with 2-alkoxyor 2-aryloxy-benzoyl chloride and following introduction of a halogen atom into the benzene nucleus of the benzamido group or the introduction of a correspondingly substituted thio-benzoyl group and the conversion of the reaction product into the corresponding benzamide derivative.

With regard to the reaction conditions, the manner of carrying out the process of the present invention may, in general, vary within wide limits and can be adapted to each individual case. For example the reactions may be carried out with the use of solvents, at room temperature or at an elevated temperature.

As starting substances, there may be used compounds containing a benzene radical substituted by the group Asthe part of this formula there may be mentioned -oo- -co- Q methyl-cyclohexyD-urea provoke after 3 hours a blood sugar lowering of 25 percent; and afler 24 hours the lowering amounts to still 25 percent, whereas the known N-(4-methylbenzenesulfonyl)-N-butyl ureas, when administered to rabbits in doses of less than 25 mg.lkg., does not provoke a lowering of the blood sugar level. The strong hypoglycemic action of the benzene-sulfonyl-ureas of the present invention becomes more evident if the dose is further reduced. When N- [4-(B- 2-phenoxy-5-methyl-benzamido -ethyl)-benzenesulfonyl]-N'-cyclohexyl-urea is administered to rabbits in a dose of 0.05 mg./kg. and N-[4-(B- 2-phenoxy-benzamido ethyl)-benzenesulfonyl]-N'-cyclohexyl-urea is administered to rabbits in a dose of 0.06 mg./kg., a distinct lowering of the blood sugar can still be observed The benzenesulfonyl-ureas described are preferably used for the manufacture of orally administrable pharmaceutical preparations for the lowering of the blood sugar level in the treatment of diabetes mellitus; they may be used as such or in the fonn of their physiologically tolerable salts or in the presence of substances which cause such salt formation. For the fonnation of salts, there may be used, for example, alkaline agents such as alkali metal hydroxides or alkaline earth metal hydroxides, alkali metal carbonates or bicarbonates or alkaline earth metal carbonates or bicarbonates which are commonly used in the pharmaceutical industry to form physiologically tolerable salts.

The invention, therefore, also provides pharmaceutical preparations of the above kind which comprise a benzenesulfonyl-urea of the present invention in admixture or conjunction with a pharmaceutically suitable carrier.

The pharmaceutical preparations are advantageously in the form of tablets containing, in addition to the products of the present invention, the usual pharmaceutically suitable carriers such as talc, starch, lactose, tragacanth or magnesium stearate.

A pharmaceutical preparation containing one of the aforesaid benzenesulfonyl-ureas as the active substance, for example, a tablet or a powder, with or without the aforesaid carriers, is advantageously brought into a suitable unit dosage form. The dose chosen should comply with the activity of the benzenesulfonyl-urea used and the desired effect. Advantageously, the dosage per unit amounts to about 0.5 to mg., preferably 2 to 10 mg., but considerably higher or lower dosage units may also be used which, if desired, are divided or multiplied prior to their administration.

The following examples illustrate the invention, but they are not intended to limit it thereto:

EXAMPLE 1 N-[4-(3- 2-phenoxy-benzamido -ethyl)-benzenesulfonyl]-N'-cyclohexyl-urea 9.9 g. of 4-(B- 2-phenoxy-benzamido -ethyl)-benzenesulfonamide (melting point l87-l88 C., prepared from 2- phenoxy-benzoid acid chloride and 4-(B aminoethyl)- benzenesulfonamide) are suspended in a mixture of 12.5 ml. of a 2N sodium hydroxide solution and 50 ml. of acetone; 3.3 g. of cyclohexyl-isocyanate are added dropwise, at 0-5 C. to this suspension. The whole is stirred for 3 hours at room temperature, the reaction mixture is diluted with water, undissolved matter is filtered ofi and the filtrate is acidified with dilute hydrochloric acid. The N-[4-(B- 2-phenoxy-benzamido -ethyl)-benenesulfonyll-N' cyclohexyl-urea, which separates in crystalline form, melts after recrystallization from methanol at l68-l 70 C.

in analogous manner, there are obtained N-[4-(,8- 2-phenoxy-benamido -ethyl)-benzenesulfonyl1- N-(4-methylcyclohexyl)urea (trans), melting point l86l 88 C. (from methanol) and N-[ 4-(B- 2-phenoxy-benzarnido -ethyl-benzenesulfonyl 1- N-butyl urea, melting point l38-l40 C. (from methanol); from 4-( B- 2-( 4-methyl-penoxy )-benzamido -ethyl benzene-sulfonamide (melting point l76-l 77 C.

N-[4-(B- 2-(4-methyl-penoxy)-benzamido -ethyl)- benzenesulfonyl]-N'-(4-methyl-cyclohexyl)-urea (trans), melting point l74-l 76 C. (from methanol);

from 4-(B- 2-phenoxy-4-chloro-benzamido ethyl)benzenesulfonamide (melting point 19 1- 1 92 C.

N-[4(B- 2-phenoxy-4-chloro-benzamido ethyl)benzenesulfonyl)]N'-cyclohexyl-urea, point l68-l69 C. (from methanol) and N-[4-(B- 2-phenoxy-4-chloro-benzamido -ethyl)- benzenesulfonyl]-N'-(4-methyl-cyclohexyl )-urea (trans), melting point l55l 56 C. (from methanol);

from 4-(B- 2-(4-methyl-phenoxy)-4-chloro-benzamido ethyl)-benzenesulfonamide (melting point l89l90 C.

melting benzenesulfonyl l-N 4-methyl-cyclohexyl )-urea (trans),

melting point l43-l45 C. (from methanol);

from 4-(13- 2-phenoxy-5-nitro-benzamido ethyl benzenesulfonamide (melting point 159- 1 60 C.

N[4-(B- 2-phenoxy-5-nitro-benzamido ethylbenzenesulfonyl]-N'-cyclohexyl-urea, melting l34l 36 C. (from methanol) and N-[4-( B- 2-phenoxy-5-nitro-benzamido -ethyl)- benzenesulfonyl] -N 4-methyl-cyclohexyl )-urea (trans), melting point l67-l 69 C. (from methanol).

point EXAMPLE 2 N-[4-(B- 2-phenoxy-5-methyl-benzamido -ethyl)- benzenesulfonyl -N '-cyclohexyl-urea 9.4 g. of N-[4-(B- 2-phenoxy-5-methylbenzamido ethyl )-benzenesulfonyl l-methyl-urethane (melting point l65-l67 C.) are suspended in 150 ml. of xylene; 2 g. of cyclohexylamine are added at 80 C. to this suspension. The whole is then heated to l40 C., while stirring vigorously, and kept for one hour at this temperature, during which time the methanol formed separates by distillation. After cooling, the solvent is decanted and the oily residue is triturated with methanol. The crystals thus obtained, constituting N-[4-(B- 2-phenoxy-5-methyl-benzamido -ethyl)-benzenesulfonyl]- N'-cyclohexyl-urea, are recrystallized from methanol and melt at l29--l31C.

In analogous manner, there is obtained N-[4-(B- 2-phenoxy-5-methyl-benzamido 'ethyl)- benzenesulfonyl]-N'-(4--ethyl-cyclohexyl)-urea (trans), melting point l53-l 54 C. (from methanol).

EXAMPLE 3 7.4 g. of N,N-diphenyl-N'-cyclohexylurea and 10.5 g. of the sodium salt of 4-(fi- 2-phenoxy-benzamido -ethyl) benzenesulfonamide are heated for 7 hours in an oil bath to 100 C, in 25 ml. of dimethylformarnide. When the solution has cooled, it is combined with water, sodium hydroxide solution is added and the diphenyl-amine that has formed is extracted with ether. The aqueous solution is filtered and acidified with dilute hydrochloric acid. The reaction product is separated by filtration with suction and recrystallized from methanol. N-[4-(B- 2phenyloxy-benzamido -ethyl)-benzenesulfonyl -N'-cyclohexylurea melts at 168l 70C.

EXAMPLE 4 N-[4-(B- 2phenoxy-benzamido -ethyl)-benzenesulfonyl]- N'-cyclohexyl-urea a. 2 g. of N-[4-()8- 2-phenoxy-benzamido ethyl)- benzenesulfonyl]-N'-cyclohexyl-thiourea (melting point l48l50 C., from a mixture of methanol and dioxane, prepared from 4-(B- 2-phenoxy-benzamido -ethyl) benzenesulfonamide and cyclohexyl isothiocyanate by boiling in acetone in the presence of potassium carbonate) are dissolved in a mixture of 40 ml. of dioxane and 40 ml. of a 2N sodium hydroxide solution. 1 g. of mercury oxide is added and the whole is stirred for 4 hours at about 60 C. When the reaction mixture has cooled, the mercury sulfide that has formed is removed by filtration with suction, the filtrate is diluted with water and acidified. A crystalline precipitate constituting N-[4- (B- 2-phenoxy-benzamido -ethyl-benzene-sulfonyl]- N'-cyclohexyl-urea is obtained which is filtered off with suction, washed with water and recrystallized from methanol. The substance melts at l68l 70 C.

b. 2 g. of N-[4-(B- 2-phenoxy-benzamido -ethyl)- benzenesulfonyl]-l l-cyclohexyl-thiourea are added, while stirring, to 40 ml. of a 2N sodium hydroxide solution. The suspension thus obtained of the sodium salt of the sulfonyl-thiourea that has formed is combined with 10 ml. of hydrogen peroxide having a strength of 35 percent and the whole is heated for 30 minutes on the steam bath. The reaction mixture is cooled, acidified with dilute hydrochloric acid and the precipitate constituting N-[4- (,B 2-phenoxy-benzamido -ethyl)-benzenesulfonyl]- N-cyclohexyl-urea is filtered 017 with suction. After washing with water the substance is recrystallized from methanol. Melting point l68-l 70 C.

EXAMPLE 5 N-[4-(B- 2-phenoxy-benzamido -ethyl)-benzenesulfonyl ]-N'-cyclohexyl-urea a. 5.4 g. of N-[4-(B- 2-phenoxy-benzamido -ethyl)- benzene-sulfonyH-N'-cyclohexyl-thiourea are dissolved in 250 ml. of methanol. 2.16 g. of mercury oxide and a pinch of potassium carbonate are added and the whole is heated, while stirring and under reflux, to the boiling temperature. After 4 hours the mercury sulfide that has formed is separated by filtration with suction and the filtrate is concentrated.

The residue obtained constituting N-[4-(B- 2-phenoxybenzarnido -ethyl)-benzenesulfonyl]-N'-cyclohexyl-isourea methyl ether crystallizes upon standing overnight. After recrystallization from dilute methanol the substance melts at 9294 C.

b. l g. of the N-[4-(B- 2-phenoxy-benzamido -ethyl)- benzenesulfonyl]-N-cyclohexyl-isourea methyl ether obtained according to (a) are dissolved in a mixture of 20 ml. of dioxane and ml. of a 2N sodium hydroxide solution. The whole is heated for 4 hours, while stirring and under reflux, to 90 C., poured into water and acidified. The precipitate obtained constituting N-[4-(B- 2- phenoxy-benzamido -ethyl )-benzenesulfonyl ]-N'- cyclohexyl-urea melts at l68l70 C. after recrystallization from methanol.

EXAMPLE 6 N-[4-(fl- 2-phenoxy-benzamido -ethyl)-benzenesulfonyl -N '-cyclohexyl-urea a. 9.9 g. of 4-(13- 2-phenoxy-benzamido -ethyl)- benzenesolfonamide are suspended in 30 ml. of ethanol having a strength of 98 percent. A solution of 2.43 g. of potassium cyanate in 5 ml. of water is added and the whole is heated, for 2% hours and under reflux, to the boiling temperature. After about 30 minutes a clear solution is obtained from which crystals separate. After standing overnight, the crystal magma is combined with a large quantity of ammonia having a strength of 1 percent, whereupon the magma is almost completely dissolved. The solution is filtered with animal charcoal and acidified. The precipitate obtained, constituting N-[4-(B- 2-phenoxy-benmmido -ethyl )-benzenesulfonyl ]-urea is filtered off with suction and recrystallized from dilute methanol. The dried substance melts at l-l57 C.

b. 4.39 g. of the N-[4-(B- 2-phenoxy-benzamido -ethylbenzenesulfonyll-urea obtained according to (a) are suspended in 40 ml. of dioxane, to this suspension 40 ml. of dimethylformamide and l g. of cyclohexylamine are added. The whole is heated for about 4 hours and under reflux to the boiling temperature, poured into a large quantity of ammonia having a strength of 1 percent and the solution thus obtained is acidified with hydrochloric acid.

The precipitate constituting crude N-[4-(fl- 2-phenoxybenzamido -ethyl)-benzenesulfonyl]-N'-cyclohexyl-urea is filtered off with suction and recrystallized from methanol. Melting point l68-l 70 C.

EXAMPLE 7 N-[4-('y- -2-phenoxy-5-nitrobenzamido propyl)benzenesulfonyl]-N'-cyclohexyl-urea 16 g. of N[4-(7-acetamido-propyl)-benzenesulfonyl]-N'- cyclohexyl-urea are heated for 3 hours to 120 C. with 100 ml. of NaOH having a strength of 10 percent. After cooling the resulting mixture is acidified, filtered and the clear filtrate is neutralized by the addition of sodium bicarbonate. The N-[4- (y-amino-propyl)-benzenesulfonyl]-N-cyclohexyl-urea that has precipitated is recrystallized from aqueous methanol and melts at 188 C.

10 g. of this sulfonyl-urea are stirred for 12 hours, at 3540 C., with 6.6 g. of 2-chloro-5-nitro-benzoyl-chloride and g. of pyridine in 80 ml. of chloroform. After removal of the chloroform under reduced pressure, the residue is dissolved in an aqueous soda solution having a strength of 1 percent, the solution is shaken with ether and acidified with hydrochloric acid. The N-[4-('y- -2-chloro-5-nitro-benzamido -propyl)- benzenesulfonyl]-N'-cyclohexyl-urea obtained is recrystallized from methanol and melts at 176 C.

5 g. of this sulfonyl-urea are dissolved in 70 ml. of glycol monomethyl ether and this solution is combined with 3.7 g. of phenyl sodium; the whole is then heated for 30 minutes to 125 C. After cooling, the solution is poured into weakly hydrochloric ice water, the precipitate that has separated is extracted with ammonia having a strength of 1 percent, acidified again and recrystallized from ethanol. N-[4-(y- -2- phenoxy-S-nitro-benzamido -propyl-benzenesulfonyl]-N'- cyclohexylurea melts at 90-92 C.

EXAMPLE 8 N-[4-(l3- 2-phenoxy-benzamido -ethyl)-benzenesulfonyl]-N'-(2,5-ethy1)-benzenesulfonyl] 6 g. of N-[4-(B- 2-phenoxy-benzamido -ethylbenzenesulfonyl -N'-(2,5-endornethylene-cyclohexylmethyl)-thiourea (melting point l83-l85 C., from dilute methanol, prepared by boiling for several hours 4-(B- 2- phenoxy-benzamido ethyl)-benzenesulfonamide with 2,5-endomethylene-cyclohexyl-methyl isothiocyanate in dioxane in the presence of potassium carbonate) are suspended in 100 ml. of a 2N sodium hydroxide solution. ml. of hydrogen peroxide having a strength of 35 percent are added and the whole is heated for 30 minutes on the steam bath. After cooling, the reaction solution is acidified, the crystal magma is filtered ofl with suction, washed with water and taken up in ethyl acetate. After separation of an aqueous layer, diisopropyl ether is added. The smeary product that has precipitated is separated by decanting the mixture of ethyl acetate and diisopropyl ether; it is then recrystallized from methanol. The N-[4-(B- 2phenoxy-benzamido -ethyl)-benzenesulfonyl}- N-(2,5-endomethylene-cyclohexyl-methyl)-urea thus ob tained melts at l38-l 40 C.

. W EXAMPLE 9 N-[4-(,B- 2-phenoxy-benzarnido -ethyl)-benzenesulfonyl]-N'-cyclohexyl-urea 5.4 g. of N-[4-(B- 2-phenoxy-benzamido -ethyl)- benzenesulfonyl]-N'cyclohexyl-thiourea are dissolved in 60 ml. of methanol. An excess quantity of methyl iodide is added and the whole is heated, for 45 minutes under reflux, to the boiling temperature and subsequently concentrated under reduced pressure. The residue constituting N-[4-(B- 2- phenoxy-benzamido -ethyl-benzenesulfonyll-isothiourea methyl ether is dissolved in methanol. 0.54 g. of sodium methylate are added and the whole is heated for 2 hours under reflux to the boilihg temperature, poured into water and acidified with acetic acid. A crystalline precipitate constituting N-[4-(B- 2-phenoxy-benzamido -ethyl-benzenesulfonyl]-N'-cyclohexyl-urea is obtained which is filtered off with suction and dried. The substance melts at l68-l70 C., after recrystallization from methanol.

We claim:

1. A benzenesulfonyl-urea of the formula in which R is alkyl of two to eight carbon atoms, cycloalkyl of five to eight carbon atoms in the ring, lower alkyl-cyclohexyl, endoalkylene-cyclohexenyl or endoalkylene-cyclohexylmethyl having one to two carbon atoms in the endoalkylene moiety; Y is an alkylene of one to four carbon atoms; Z is phenyl or p-tolyl; and X is hydrogen, methyl, ohloro or nitro substituted in the 4- or S-position; or a salt thereof of a pharmaceutically acceptable base.

2. Benzenesulfonyl-ureas as claimed in claim 1, in which X is chlorine in S-position to the carbon-amide group.

3. Benzenesulfonyl-ureas as claimed in claim 1, in which R is cyclohexyl.

4. Benzenesulfonybureas as claimed in claim 1, in which R is 4-rnethyl-cyclohexyl.

5. Benzenesulfonyl-ureas as claimed in claim 1, in which X is methyl in 5-position.

6. Benzenesulfonyl-ureas as claimed in claim 1, in which phenylene" is unsubstituted p-phenylene.

7. Benzenesulfonyl-ureas as claimed in claim 1, in which Y is dimethylene.

8. N-[4-(,B- 2-phenoxy-benzamido -ethyl)-benzenesulfonyl1-N'-(4-methyl-cyclohexyl)-urea.

9. N-[4-(fi- 2-phenoxy-5-methyl-benzamido -ethyl)- benzenesulfonyl1-N-cyclohexyl-urea.

110. N-[4-(5- 2-phenoxy-benzamido -ethyl)-benzenesulfonyl]-N-cyclohexyl-urea.

ll. N-[4-(B- 2-phenoxy-4-chloro-benzamido -ethyl benzenesulfonyl]-N'-(4methyl-cyclohexyl)-urea.

l2. N-[4-(B' 2-phenoxy-S-chloro-benzamido -ethyl)- benzenesulfonyl]-N-(4-methyl-cyclohexyl)-urea. 

2. Benzenesulfonyl-ureas as claimed in claim 1, in which X is chlorine in 5-position to the carbon-amide group.
 3. Benzenesulfonyl-ureas as claimed in claim 1, in which R1 is cyclohexyl.
 4. Benzenesulfonyl-ureas as claimed in claim 1, in which R1 is 4-methyl-cyclohexyl.
 5. Benzenesulfonyl-ureas as claimed in claim 1, in which X is methyl in 5-position.
 6. Benzenesulfonyl-ureas as claimed in claim 1, in which ''''phenylene'''' is unsubstituted p-phenylene.
 7. Benzenesulfonyl-ureas as claimed in claim 1, in which Y is dimethylene.
 8. N-(4-( Beta -<2-phenoxy-benzamido>-ethyl)-benzenesulfonyl) -N''-(4-methyl-cyclohexyl)-urea.
 9. N-(4-( Beta -<2-phenoxy-5-methyl-benzamido>-ethyl)-benzenesulfonyl)-N''-cyclohexyl-urea.
 10. N-(4-( Beta -<2-phenoxy-benzamido>-ethyl)-benzenesulfonyl)-N''-cyclohexyl-urea.
 11. N-(4-( Beta -<2-phenoxy-4-chloro-benzamido>-ethyl)-benzenesulfonyl)-N''-(4methyl -cyclohexyl)-urea.
 12. N-(4-( Beta -<2-phenoxy-5-chloro-benzamido>-ethyl)-benzenesulfonyl)-N''-(4-methyl -cyclohexyl)-urea. 